Morin Exerts Anti‐Arthritic Effects by Attenuating Synovial Angiogenesis via Activation of Peroxisome Proliferator Activated Receptor‐γ

Scope Morin, a flavonoid occurring in many dietary plants, can reduce the number of synovial blood vessels and ameliorate collagen‐induced arthritis (CIA) in rats. Herein, its underlying mechanisms in view of the peroxisome proliferator activated receptor‐γ (PPARγ) pathway are addressed. Methods and results In vitro, wound‐healing and transwell assays are conducted to explore the effect of morin on HUVECs migration. Morin inhibits HUVECs migration and tube formation induced by VEGF, which is reversed by PPARγ antagonist GW9662 or siPPARγ. Molecular docking and competitive binding assays show that morin could bind to PPARγ. Morin increases the expression of PDK4 and CD36 in a PPARγ‐dependent manner and increases the luciferase activity in cells transfected with PPARγ plasmid, which indicates that morin could activate PPARγ after binding. In addition, morin increases the expression of PTEN, a target gene of PPARγ that suppresses angiogenesis and inhibits PI3K/Akt signaling. The effects of morin on the PTEN‐PI3K/Akt pathway are diminished by GW9662 and siPPARγ. In vivo studies show that morin ameliorates rat CIA, reduces synovial angiogenesis, and upregulates the expression of PTEN in the synovium, which is almost completely abolished by GW9662. Conclusions Morin is a potential agonist of PPARγ, which attenuates synovial angiogenesis and arthritis via the PPARγ‐PTEN‐PI3K/Akt pathway. Morin, a flavonoid occurring in many dietary plants, can ameliorate collagen‐induced arthritis in rats. It is shown that morin suppresses synovial angiogenesis and collagen‐induced arthritis by activating PPARγ, enhancing the expression of PTEN, and subsequently inhibiting the PI3K/Akt signaling pathway. To our knowledge, this is the first report identifying morin as a PPARγ agonist that prevents synovial angiogenesis and arthritis.